This application relates to a system and method for monitoring and/or controlling patient diabetes-related blood constituents.
The number of diabetes mellitus (DM) patients in the U.S. in 1993 was estimated to be 7.8 million persons (roughly 3.4% of the total US population). The number of patients with diabetes mellitus has steadily grown over the last 25 years (Diabetes 1996: Vital Statistics. American Diabetes Association Inc., 1996). See FIG. 1 (U.S. Diabetes Mellitus prevalence data 1993 adapted from Diabetes Vital Statistics, American Diabetes Association 1993).
From this total, 10% (or about 0.8 million persons) are estimated to be insulin dependent diabetes mellitus (IDDM) patients. The Diabetes Control and Complications Trial (the DCCT) showed a 70% reduction in complications resulting from tight metabolic control in IDDM patients. See xe2x80x9cThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitusxe2x80x9d, The Diabetes Control and Complications Trial Research Group, The New England Journal of Medicine, Vol. 329, No 14. Sep. 30, 1993. The DCCT underscores the importance of developing a better way to control blood glucose for the IDDM patient group. Unfortunately, the study showed substantial evidence that the frequency of hypoglycemic excursions increases 2-3 times in IDDM patients subjected to tight metabolic control compared to regular treatment. Frequent hypoglycemic excursions additionally create hypoglycemic unawareness, a state where patients become incapable of recognizing themselves the usual symptoms associated with hypoglycemia.
In the U.S. diabetes mellitus (DM) population, 90% (or 7 million persons) are estimated to be non-insulin dependent diabetes mellitus (NIDDM) patients. NIDDM patients may be subdivided into insulin users (30%, or 2.3 million persons), of which at least 25% (or 0.52 million persons) measures their blood glucose levels on a daily basis. The percentage of NIDDM patients receiving insulin treatment increases with the duration of NIDDM from 25% (0-4 years) to 60% ( greater than 20 years). It is estimated that the diagnosed number of NIDDM patients reflects only about 50% of the actual population suffering from NIDDM. However, it is recognized that only a limited percentage of this group requires improved treatment. The remainder of the NIDDM population generally self manages the disease though careful meal planning and exercise, or by means of oral hypoglycemic agents.
Comprehensive diets and injective insulin administration, combined with glucose level determination multiple times a day, may provide an acceptable degree of metabolic control, but often fall short of being optimum and may also induce considerable patient discomfort. Injected insulin does not enter the circulation directly, resulting in a delayed and reduced effect in bringing plasma glucose level down to acceptable values. Increased and prolonged hyperglycemic and/or hypoglycemic periods contribute to chronic complications. Ocular complications such as cataracts and retinopathy occur in approximately 50% of such patients after ten years. Severe nephropathy, neuropathy, and gangrene of the feet and skin complications are frequently observed.
Hypoglycemic medication, such as the sulfonylureas class of drugs, directly potentiate the release of insulin from vital pancreatic beta-cells. Severe hypoglycemia is frequently reported as a side effect of this type of drugs. More recent families of hypoglycemic agents such as biguanides and acarbose reduce the hypoglycemic threat but have a limited therapeutic scope and have undesirable side effects, which include nausea, abdominal pain and diarrhea.
A relationship between diabetes mellitus and coronary heart disease has long been suggested. See Garcia, M. J. et al., xe2x80x9cMorbidity and Morality in Diabetics in the Framingham Population: Sixteen Year Follow-Up Study,xe2x80x9d Diabetes, 23:105-11 (1974); Fein, F. S., xe2x80x9cHeart Disease In Diabetes,xe2x80x9d Cardiovasc. Rev. Rep., 3:877-93 (1982); xe2x80x9cRelationship of Glucose Tolerance to Prevalence of ECG Abnormalities and to Annual Mortality From Cardiovascular Disease: Results of the Paris Prospective Study,xe2x80x9d Ducimetiere et al., J. Chron. Dis., Vol. 32, pp. 759 to 766 (1979). Additionally, a correlation between a patient""s ECG and blood potassium levels, and variations in the ECG following introductions of insulin, have been recognized. See Heine et al., Acta Endocrinologica 1984, 106:241-247.
The field of glucose monitoring is active. Its importance lies in indicating to the diabetic when and how much insulin should be taken. Ideally, glucose monitoring would be continuous and non-invasive. With an accurate continuously monitoring glucose sensor, information would constantly be available, either to signal a condition of hyperglycemia or hypoglycemia, or even direct and enable a closed loop system by which insulin would be automatically delivered so as to keep glucose levels close to normal physiological levels. Such a system would reduce chronic complications and provide an obvious increase in quality of life for IDDM patients.
A closed loop control system driven by a glucose sensor would enable the delivery of accurate amounts of insulin, keeping glucose levels near physiological levels while constantly monitoring upcoming hypoglycemic hazards. The key component missing in such a system is a reliable, accurate and biocompatible glucose sensor. Compared to the IDDM population, the NIDDM population is very heterogeneous in age, therapy, and stage of the disease.
Most glucose sensors presently in common use are based on electrochemical methods such as the electro-enzymatic method where blood glucose is oxidized under glucose-oxidase control, producing gluconic acid and hydrogen peroxide. By using this enzymatic reaction as a first stage, the problem is reduced to a measurement of used oxygen or produced hydrogen peroxide (i.e., the amperometric method). Alternately, the produced gluconic acid can be determined directly (i.e., the potentiometric method). Both sensor types suffer from stability problems, however. Optical glucose sensors have been experimented with, but for several reasons are not feasible for long term continuous monitoring, and especially not for implantable glucose monitoring applications.
Patents and printed publications describing various aspects of the foregoing problems and the state of the art are listed below.
U.S. Pat. No. 3,877,873 entitled xe2x80x9cTest for Metabolic Conditions in Blood or Serumxe2x80x9d to Winitz
U.S. Pat. No. 4,408,905 entitled xe2x80x9cUrinary Temperature Measurement Devicexe2x80x9d to Ehrenkranz.
U.S. Pat. No. 4,476,901 entitled xe2x80x9cApparatus for Improving Blood Sugar Control in Diabeticsxe2x80x9d to Kraegen et al.
U.S. Pat. No. 4,776,842 entitled xe2x80x9cDevice for the Administration of Medicationsxe2x80x9d to Franetzki et al.
U.S. Pat. No. 4,731,051 entitled xe2x80x9cProgrammable Control Means for Providing Safe and Controlled medication Infusionxe2x80x9d to Fischell.
U.S. Pat. No. 4,871,351 entitled xe2x80x9cImplantable Medication Infusion Systemxe2x80x9d to Feingold.
U.S. Pat. No. 5,190,041 entitled xe2x80x9cSystem for Monitoring and Controlling Blood Glucosexe2x80x9d to Palti.
U.S. Pat. No. 5,231,988 entitled xe2x80x9cTreatment of Endocrine Disorders by Nerve Stimulationxe2x80x9d to Wernicke.
U.S. Pat. No. 5,368,028 entitled xe2x80x9cSystem for Monitoring and Controlling Blood and Tissue Constituent Levelsxe2x80x9d to Palti.
U.S. Pat. No. 5,540,734 entitled xe2x80x9cCranial Nerve Stimulation Treatments Using Neurocyberetic Prosthesesxe2x80x9d to Zabara.
U.S. Pat. No. 5,741,211 entitled xe2x80x9cSystem and Method for Continuous Monitoring of Diabetes-related Blood Constituentsxe2x80x9d to Renirie et al.
U.S. Pat. No. 5,844,862 entitled xe2x80x9cSkin Temperature Radio Telemetry and Alarmsxe2x80x9d to Cocatre-Zilgien.
U.S. Pat. No. 5,919,216 entitled xe2x80x9cSystem and Method for Enhancement of Glucose Production by Stimulation of Pancreatic Beta Cellsxe2x80x9d to Houben et al.
Alvestrand, A., Wahren, J., Smith, D., and DeFronzo, R. A. Insulin-mediated potassium uptake is normal in uremic and healthy subjects. Am. J.Physiol. 246:E174-80, 1984.
Anderson, E. A., Hoffman, R. P., Balon, T. W., Sinkey, C. A. and Mark, A. L. (1991) Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J. Clin. Invest. 87, pp. 2246-2252.
Berne, C., Fagius, J. and Niklasson, F. (1989) Sympathetic response to oral carbohydrate administration. Evidence from microelectrode nerve recordings. J. Clin. Invest. 84, pp. 1403-1409.
Berne, C. and Fagius, J. (1993) Metabolic regulation of sympathetic nervous system activity: lessons from intraneural nerve recording. International Journal of Obesity 17 (suppl 3), S2-S6.
Dear H D, Buncher C R, Sawayama T. (1969) Changes in electrocardiogram and serum potassium values following glucose ingestion. Arch Internal Medicine 124, pp. 25-28.
DeFronzo R A, Felig P, Ferrannini E, Wahren J, Effect of graded doses of Insulin on splanchic and peripheral potassium metabolism in man. Am. J. of Physiol. 238 (Endocrin. Metab. 1): E421-27, 1980
Frandsen, H., Fagius, J., Nikklasson, F., (1990) Muscle sympathetic nerve response after oral glucose is attenuated in type I diabetes. Diabetologica 33, A165.
Heinemann L, Meinhold J, Kunze W. (1995) Hypoglycemia detection be ECG recording?. Diabetes Care 18 no 1, p139-140.
Heger G; Howorka K; Thoma H; Tribl G; Zeitlhofer J (1996) Monitoring set-up for selection of parameters for detection of hypoglycaemia in diabetic patients, J Med Biol Eng Comput, January 1996, 34:1, 69-75
Howorka K; Heger G; Schabmann A; Anderer P; Tribl G; Zeitlhofer J (1996) Severe hypoglycaemia unawareness is associated with an early decrease in vigilance during hypoglycaemia, Psychoneuroendocrinology, Apr, 21:3, 295-312
Joslin""s Diabetes Mellitus, thirteenth edition, Gordon Weir, Ronald Kahn, 1994, ISBN 0-8121-1531-7
Katz, A. M., Physiology of the Heart, Raven Press, New York 1977.
Kern, W., Schlosser, C., Kerner, W., Pietrowsky, R., Born, J. and Fehm, H. L. (1994) Evidence for effects of insulin on sensory processing in humans. Diabetes 43, 351-356.
Kreagen, E W., Chisholm D J, (1988) Closure of the loop by glucose sensing, Physiological and practical considerations. Implantable glucose sensors, The State of the Art International Symposium Reisenburgt. Hormone and Metabolic Research Vol. 20, 1-4
Marques J L; George E; Peacey S R; Harris N D; Macdonald I A; Cochrane T; Heller S R (1997) Altered ventricular repolarization during hypoglycaemia in patients with diabetes, Diabet Med, 14:8, 648-54
Minaker-K L; Meneilly-G S; Flier-J S; Rowe-J W, Insulin-mediated hypokalemia and paralysis in familial hypokalemic periodic paralysis. Am J. of Med. June 1988; 84(6): 1001-6
Ostrander L D, Weinstein B J. (1964) Electrocardiographich changes after glucose ingestion. Circulation 30, pp. 67-76.
Parrish A E, Sugar S J, Fazekas J F. (1952) A relationship between electrocardiographich changes and hypokalemia in insulin-induced hypoglycemia. American Heart Journal. pp. 815-821.
Petersen K G, Schluter K J, Kerp L. (1982) Regulation of serum potassium during insulin-induced hypoglycemia. Diabetes 31, pp. 615-617.
Rowe, J. W., Young, J. B., Minaker, K. L., Stevens, A. L., Pallotta, J. and Landsberg, L. (1981) Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes 30, 219-225.
Riley C P, Oberman A, Sheffield L T (1972) Electrographic effects of glucose ingestion. Arch Internal Medicine 130 pp.703-707.
Spraul, M., Anderson, E. A., Bogardus, C. and Ravussin, E. (1994) Muscle sympathetic nerve activity in response to glucose ingestion. Impact of plasma insulin and body fat. Diabetes 43, 191-196.
Teagtmeyer H, Russel R R III, Biochemistry of the heart, Current concepts in cardiovascular physiology 2-61
Tribl G; Howorka K; Heger G; Anderer P; Thoma H; Zeitlhofer J (1996) EEG topography during insulin-induced hypoglycemia in patients with insulin-dependent diabetes mellitus, Eur Neurol, 36:5, 303-9.
Zierler K, Rogus E M. (1980) Hyperpolarization as a mediator of insulin action: increased muscle glucose uptake induced electrically. American Journal of Physiology 239 (Endocrine metabolism 2) pp. E21-29.
Zierler K., Rogus E M. (1981) Rapid hyperpolarization of rat skeletal muscle induced by insulin. Biochimica et Biophysica Acta 640, 687-692.
Zierler K., Rogus E M, Scherer R W, Wu FS. (1985) Insulin action on the membrane potential and glucose uptake: Effects of high potassium. Am. Journal of Physiology 249: E17-25.
All patents and printed publications listed hereinabove are hereby incorporated by reference herein, each in its respective entirety. As those of ordinary skill in the art will appreciate readily upon reading the Summary of the Invention, Detailed Description of the Preferred Embodiments and Claims set forth below, at least some of the devices and methods disclosed in the patents and publications listed hereinabove may be modified advantageously in accordance with the teachings of the present invention.
It will now be seen that there exists a need for a system capable of continuously monitoring blood constituents from which patient insulin or other beneficial agent need may be determined, a system capable of determining and indicating such a need, and a system capable of automatically delivering at least one beneficial agent in response to such a determination or indication and/or alerting the patient that a dangerous situation may be developing. There further exists a need for a system capable of quickly, reliably and accurately determining that a hypoglycemic state exists in a patient. Finally, there exists a need for a system capable quickly, reliably and accurately determining that the onset of a hypoglycemic state in the patient is imminent, and alerting the patient, a health care giver or emergency service of same.
The present invention has certain objects. That is, the present invention provides solutions to problems existing in the prior art. It is an object of the present invention to provide a system and method for continuous sensing of hypo- or hyper-glycemic state, the rate of change of blood glucose levels in respect of time, and/or blood insulin and/or blood glucose levels, the system being wearable by a patient or implantable therein. Another object of the present invention is to provide a sensor which is capable of detecting changes in blood insulin and/or glucose based upon the processing of ECG and EEG signals, and which provides a reliable correlation between monitored ECG and EEG parameters and insulin and/or glucose levels.
Various embodiments of the present invention have advantages, including one or more of the following: (a) improving the degree of direct or indirect control that may be exercised over the blood glucose and/or insulin levels of a diabetic patient; (b) providing timely notification to a patient or health care provider that the patient is about to enter or has entered into a hypoglycemic state; (c) providing timely notification to a patient or health care provider that the patient is about to enter or has entered into a hyperglycemic state; (d) quickly delivering a beneficial agent to a patient before a hypoglycemic or hyperglycemic state develops or becomes dangerous; (e) continuously updating and adapting its control program so that more reliable and accurate predictions of a hypoglycemic and/or hyperglycemic state may be made; (f) increased accuracy in the detection and prediction of a hypoglycemic and/or hyperglycemic state; (g) overcoming the deficiencies of relying on ECG or blood glucose data alone when detecting the presence or onset of a hypoglycemic state and/or a hyperglycemic state; (h) increasing patient safety and lowering health care costs owing to better control of patient blood glucose and/or insulin levels.
Various embodiments of the system of the present invention have certain features. We discovered that information derived from ECG signals and EEG signals may be successfully employed in combination to reliably predict the onset, or to indicate the presence of, hypoglycemia. Direct or indirect monitoring of blood glucose levels may additionally be employed to detect hyperglycemia, and in response to detection of a hyperglycemic state output an alarm signal or cause insulin to be delivered to the patient.
In one system of the present invention, ECG and EEG signals are processed and the information derived from them is combined to determine whether a patient suffering from diabetes is undergoing a hypoglycemic event, or whether such an event is imminent. Input data from the patient, a health care provider or one or more sensors may also be used to increase the accuracy and reliability of the system. Detection of a hypoglycemic or hyperglycemic event by the system can result in an alarm signal being output, and the delivery or administration of a beneficial agent such as insulin, glucagon or diazoxide. The system may be implantable, external, or a combination of external and implantable components. The control strategy of the present system is preferably microprocessor based and/or implemented using dedicated electronics.
Alternatively, the present invention may comprise an open loop control system in which the delivery of a beneficial agent to the patient in response to an alarm signal being generated is not feedback controlled by an on-line insulin level determination, for example. In an open loop system of the present system insulin or other beneficial agent delivery is based on a predetermined or preprogrammed schedule. It has been established that in a healthy person, the insulin levels are elevated even before the blood glucose level rises, due to neural factors and the involvement of gut hormone levels. During meal periods, open loop systems perform better than closed loop systems, due to the capability of starting the insulin rate increase during and even before meal ingestion. Accordingly, it is anticipated that the invention may be adapted to a system which is closed loop controlled generally, but open loop controlled in accordance either with a programmed time schedule, or in response to external programming by the patient.
The hypoglycemic and/or hyperglycemic alarms and feedback control systems of the present invention are capable of providing enhanced control of diabetes, leading to a reduction in the chronic complications of DM by as much as 70% (as indicated by the Diabetes Control and Complications Trial or DCCT, 1993). The DCCT study revealed that intensified insulin treatment decreased HbA1c levels by at least 2% and also subsequently reduced long-term microvascular complications by at least 70%, in comparison to standard treatment techniques.
Those favorable results were accomplished, however, at the cost of a twofold increase in mostly nocturnal hypoglycemic excursions, as well as increased incidence of hypoglycemic unawareness. The DCCT studies thus indicated that DM patients subjected to intensified insulin treatment were sub-optimally controlled. Later studies by Colwell (1994) and Wolffenbuttel (1995) provided similar results for NIDDM patients, where changes in medical care were found to be directly related to the improvement of HbA1c levels below 6% as a result of intensified insulin treatment. Nevertheless, and as discussed above, continuous detection of hypoglycemic threat remains an unmet clinical need.
Optimal control of patients implies reducing the long term threats of microvascular complications and nocturnal hypoglycemic events. The system of the present invention satisfies those long felt but unmet needs by providing a reliable hypoglycemia detection system that permits enhanced, tight control of blood glucose levels, and thereby reduces the risk of hypoglycemic coma within acceptable limits. Various embodiments of the system of the present invention are also capable of detecting a hyperglycemic state and responding to same (e.g., output of alarm signal or delivery of one or more beneficial agents).
Other objects, features, advantages and embodiments of the present invention will become apparent upon reading the Detailed Description of the Preferred Embodiments and the Claims.